Products and processes for the treatment of the alimentary canal

ABSTRACT

Complexes of bismuth, e.g. bismuth salts, and polyacrylate, e.g. carbomer, are discloses which may be incorporated into pharmaceutical compositions for oral, oral delayed-release, and rectal administration. The complexes may be combined with an antibiotic, such as tetracycline, and an antiprotozoal agent, e.g. Metronidazole, for use in the treatment of Helicobacter pylori infection. The treatment of inflammatory bowel disease using bismuth/polyacrylate complexes, or other bismuth preparations, is also described.

This invention relates to products and processes for the treatment ofthe alimentary canal, the use of bismuth and novel complexes thereof fortreating conditions of the alimentary canal.

Bismuth compounds have been used medically for over 150 years,originally being used in the treatment of treponeme infection, e.g.syphilis, and latterly as dusting powders, antacids, astringents and inthe treatment/prophylaxis of traveller's diarrhoea. More recently,bismuth salts have been used in the treatment of gastric and duodenalulcers. However, it is likely that such salts are precipitated in thelow pH environment of the stomach and thereby will be less likely to bebiologically active further along the gut. It has also been known to usesuppositories and ointments containing bismuth to treat haemorrhoids.

There has been a need to improve the pharmacological effectiveness ofbismuth while minimising its absorption from the gut. The desired actionof bismuth is local, and absorption leads to unwanted side-effects whichmay limit the duration, dosage or intensity of treatment.

We have discovered that bismuth forms a water soluble complex withpolyacrylates and that the soluble complexes are particularly useful intreatment of conditions of the alimentary canal. Moreover, they have theadvantage of being very poorly absorbed from the gut.

One aspect of our invention provides a water soluble complex of bismuthwith a polyacrylate.

We surmise that bismuth complexes with the anionic carboxyl groups ofthe polyacrylate and does not readily precipitate at acid pH, althoughour invention is founded on empirical evidence and not on any theory ofaction.

Preferably, the polyacrylate is a carbomer, such as those described inthe British Pharmacopoeia and defined in CAS 54182-57-9, which generallyconsists of a polymer of acrylic acid cross-linked with allylsucrose,and contains 56 to 68% carboxylic acid groups. Preferred carbomers arecarbopol 934P and 974P (available from Goodrich UK).

Until recently, carbomer has been used in the pharmaceutical andcosmetic fields as stabilisers, binding agents, emulsifiers andgel-forming excipients. In GB 2,220,855 (Reckitt & Coleman)polyacrylates of the carbomer type are suggested for use alone in thetreatment of inflammatory bowel disease.

It is noted that carbomer has been reacted with basic drugs, such asephedrine, but it has not been suggested previously that polyacrylatesmight form a soluble complex with heavy metal ions like bismuth andthereby modify their pharmacological effect and metabolic fate.

We prefer to use a bismuth salt to prepare the complex and prefer saltswith weak inorganic acids or organic carboxylic acids, e.g. selectedfrom bismuth citrate, bismuth carbonate, bismuth subsalicylate andbismuth subgallate. Bismuth hydroxide may also be used. Other salts,such as bismuth subnitrate, and bismuthates, such as tripotassiumdicitrato bismuthate, may be used. The complex preferably comprisescarbopol 934P and bismuth derived from bismuth citrate.

It is also possible to use bismuth combined with ligands, such ascoordinating ligands, and ligands or cations from the salts mentionedabove may become incorporated into the complex. It is clear thereforethat the cation or ligand used must be carefully selected since it maybe released from the complex in use.

The complex may be prepared by reacting a suitable bismuth compound,e.g. a salt with a weak acid, preferably with an aliphatic or aromaticcarboxylic acid, with a dispersion of the carbomer. If desired an acidacceptor may be present or preferably may be added subsequently tocombine with the acid liberated from said salt and produce a final pHe.g. in the range 5 to 8. For example, bismuth citrate and bismuthsubsalicylate may be used as said bismuth compound; in the case ofbismuth citrate, it is desirable to add sodium hydroxide or other acidacceptor at the end of the reaction to increase the water solubility ofthe carbomer-bismuth complex, neutralise the citric acid liberated andmaintain the pH necessary to give the desired viscosity in the carbomersolution.

The reaction may take several days e.g. 2 to 12 days standing at roomtemperature, but can be accelerated by constant stirring and heating,e.g. to 40° C. or higher. A temperature of 40° C. with stirringovernight will usually produce the complex within 24 hours. Aqueousreaction media will often be used, but non-aqueous or aqueous/organicmedia can also be used if the solubilities of the reactants areappropriately selected. Another alternative is to incorporate thebismuth in the carbomer during its preparation.

The ratio of bismuth to carbomer for the formation of soluble complexescan be varied, there being sufficient carbomer to solubilise the bismuthbut preferably not so much that over-viscous solutions are produced. Astoichiometric ratio of carboxyl groups to bismuth ions tend to resultin an unduly low viscosity of solutions containing the complex.Therefore an excess of carbomer is preferred. The weight ratio ofreactants used of course depends on the bismuth compound used and on theproportion of free carboxyl groups in the carbomer. For example, usingCarbopol 934P and bismuth citrate, the ratio may be in the range 7:1 to1:5, preferably about 2:1 by weight. If the ratio of bismuth to carbomeris too great then the carbomer becomes supersaturated. The complex soformed very readily releases bismuth in the intestine as it reachesequilibrium with intestinal fluid.

The soluble complex may be extracted by conventional techniques such as,by precipitation from an aqueous medium with a water-miscible organicsolvent e.g. methanol.

We have found that the complex according to the invention isparticularly effective in the treatment of conditions of the alimentarycanal although other conditions may be beneficially treated using apharmaceutical composition comprising a complex according to theinvention.

The complex may be incorporated into a pharmaceutical composition to beadministered either rectally, e.g. as an enema, or orally, for example,in coated tablets or capsules as described below. Also, the complex maybe formed into microgranules and coated, for example with Eudragit-L orS and contained within a capsule similarly coated. In all solidcompositions it is preferable to include a disintegrant. Still further,bismuth/polyacrylate complexes may be formulated in a number of dosageforms, e.g. uncoated or coated solid dosage forms for non-delayedrelease or delayed release oral administration.

Upper alimentary conditions of interest, include for example, pepticulcer of the oesophagus, stomach or duodenum and mucosal inflammation(oesophagitis, gastritis and duodenitis). In general, mucosalinflammation of the alimentary tract is often related to perniciousinfection with Helicobacter pylori (previously classified asCampylobacter pylori) and such infection may be successfully treatedwith bismuth preparations. Heretofore a popular treatment ofHelicobacter pylori infection has required four daily doses of bismuthtablets, tetracyline tablets and metronidazole tablet (metronidazolebeing a preferred anti-protozoal drug) whereas pharmaceuticalcompositions comprising the bismuth/polyacrylate complex according tothe invention may be formulated or complexed with tetracyline andmetronidazole (2-methyl-5-nitroimidazole-1-ethanol) for only twice dailyadministration. The invention also includes therefore pharmaceuticalcompositions comprising the bismuth complex and one or more furtherpharmacologically active compounds e.g. antibiotics or anti-protozoalagents.

Some small intestinal and colonic conditions are associated withidentifiable infective organisms. Two organisms of note are Cryptococcusand Microsporidium. These organisms sometimes occur in water suppliesand cause severe diarrhoea, especially in patients with AIDS.Pharmaceutical compositions according to the invention, preferably inpost-gastric delayed release dosage form may be administered orally topatients to combat infections such as these. Other such formulations maybe prepared to take advantage of the benefits of a bismuth/polyacrylatecomplex according to the invention.

It is a notable aspect of our invention that a bismuth/polyacrylatecomplex is also particularly useful in the treatment of inflammatorybowel disease such as ulcerative colitis and Crohn's disease involvingthe colon.

Numerous compounds have been examined in the last twenty years to findeffective measures for the treatment of inflammatory bowel disease. Suchcompounds include arsenicals, disodium cromoglycate, flagyl, lignocaine,4- and 5-aminosalicylic acid as rectal preparations and orallyadministered thalidomide and cyclosporin. Rectal arsenic has been shownto be highly effective in ulcerative proctitis but is no longer widelyused and, indeed, the therapeutic use of inorganic arsenicalpreparations is no longer recommended. The wide diversity of treatmentsis an indication of the complexity and intransigence of this condition.

So far the only effective forms of medical therapy for ulcerativecolitis are corticosteroids and aminosalicylates but approximately onethird of patients fail to go into complete remission despiteconventional therapy.

In spite of many attempts to provide an effective treatment forinflammatory bowel disease, this chronic, distressing and ultimatelylife-threatening condition has not been well controlled.

Although bismuth/polyacrylate complexes appear to have distinctadvantages in the treatment of inflammatory bowel disease, we have foundthat other compounds of bismuth may also be used for this purpose. Thebismuth compound should be rectally administered, or post-gastricallyavailable, and is preferably used in combination with a stabilisingagent, to provide a novel and effective treatment of inflammatory boweldisease.

Thus a further aspect of our invention provides the use of a compoundcontaining bismuth in the preparation of a rectally administeredpharmaceutical composition or delayed-release oral composition for thetreatment of inflammatory bowel disease.

Another aspect of our invention provides a pharmaceutical compositionfor rectal administration for the treatment of inflammatory boweldisease characterized in that it comprises a compound containing bismuthand a thickening/gelling agent.

The composition may be in a form suitable for use as a fluid or foamenema, or as a concentrate for use in the preparation of an enema or inthe form of a suppository.

While it is preferred to use a bismuth/polyacrylate complex, othersalts, especially with weak or organic acids, may be used, e.g. bismuthcitrate, bismuth carbonate, bismuth subsalicylate, bismuth subgallate,or less preferably bismuth subnitrate may be used. Also, bismuthatessuch as tripotassium dicitrato bismuthate may be used.

The thickening/gelling agent may be selected from any which arepharmaceutically acceptable and thicken or form gels with aqueous media.Preferably the agent is selected from polyacrylates, e.g. carbomers,such as Carbopol 934P, although cellulose derivatives, especiallyhydroxyalkyl ethers such as hydroxypropyl, hydroxyethylmethyl, andhydroxyethyl cellulose, and gums of microbial or vegetable origin, e.g.xanthan gums, for example Keltrol may be used. Of course it will beapparent to a skilled person that the thickening/gelling agent may beselected so that it only exhibits the required thickening/gellingproperties in the conditions of the colon and rectum. In this respect itshould be noted that the viscosity of carbomer-containing aqueouscompositions may be varied by changes in pH and/or ionic strength. Thusa pharmaceutical composition according to the invention may beformulated for ease of administration yet exhibit the desiredthickening/gelling qualities once administered.

Dosage rate will depend on mode of application, dosages per day, size ofpatient etc. and will be readily determined by the skilled person. Apreferred formulation for an enema would comprise, for example, abismuth compound, e.g. bismuth citrate, in a unit dosage in the range300 mg to 1,600 mg, preferably 400 mg to 800 mg, suspended in an aqueouscarrier, preferably of about 100 ml; the formulation preferably contains0.1 to 2.0% carbomer, e.g. Carbopol 934P, more preferably 0.4 to 1.0%and desirably the bismuth and carbopol are present as a complex.

Depending on the nature of the thickening/gelling agent, it may bepreferable to use an antioxidant and/or preservative such as ametabisulphite or methyl/propyl hydroxybenzoate. The amount of such anagent will be apparent to a skilled person and, again, is dependent onthe form of administration.

Enema foams will comprise suitable foam bases containing expandingagents, surfactants and foam-stabilisers.

It is a surprising and valuable feature of our invention that absorptionof bismuth, as measured by bismuth serum levels, is minimal even afterprolonged administration.

It is also possible to provide a composition which is not administeredrectally but per os and only becomes available to the patient afterpassing through the stomach.

A further aspect of our invention provides a delayed orsubstained-release pharmaceutical composition for oral administrationcharacterized in that it comprises a compound containing bismuth whichis released post-gastrically.

In order to achieve the desired delayed or sustained-release, it ispreferable to form the composition as a tablet or capsule, e.g. agelatin capsule, having a coating of acidic material substantiallyinsoluble in the gastric fluid and of limited solubility in alkalinemedia.

A sustained-release formulation can be achieved by either using amicrogranular formulation of the bismuth compound coated with asemi-permeable membrane such as ethylcellulose or by coating thegranules with a lacquer consisting of an acrylic resin based on acrylicand methacrylic acid esters containing a low content of quaternaryammonium groups at a predetermined molar ratio. suitable resins includeEUDRAGIT RL and RS. The coated granules may then be compressed intotablets or packed into hard gelatin capsules suitable for oraladministration.

As acidic material for the coating of oral compositions of the inventionfor delayed-release anionic polymers, particularly anionic acrylatepolymers and especially anionic polymers synthesised from methacrylicacid and methyl methacrylate, may be used. Carboxyl groups in suchpolymers render the material capable of forming salts in alkalineenvironments in which they are sparingly soluble while in the acid toneutral pH range the coatings will be substantially insoluble andsubstantially impermeable thus protecting the active ingredientcontained within from gastric acids.

The coatings may be applied conventionally, typically as a lacquer orsolution containing the acidic material from which the solvent orcarrier is then evaporated.

A particularly suitable acidic material for coating the compositions ofthe invention for lower bowel treatment is the anionic methacrylatepolymer sold under the registered Trade Mark EUDRAGIT S by Rohm PharmaGmbH of Darmstadt, West Germany. Earlier investigations revealed thatcapsules coated with EUDRAGIT S100 disintegrate in the ascending colonof the patients to whom the capsules were administered. In generalEUDRAGIT S has previously been recommended only for mixture with moresoluble polymers in order to retard release, and has not been envisagedas the sole coating material. EUDRAGIT S is a copolymer of methacrylicacid and methyl methacrylate in which the ratio of free carboxyl groupsto ester groups is approximately 1:2 and having a mean molecular weightof 135,000. Coatings of acidic materials, such as that sold as EUDRAGITL (composition as EUDRAGIT S but having a carboxyl/ester ratio of 1:1),may be used in the coating of tablets or capsules to release activeagents in the small intestine, although they may be applied in muchgreater thicknesses than was hitherto conventional thereby delayingrelease of the active agent until the tablet or capsule reaches thelarge intestine. It will be apparent to the skilled person that mixturesof substances, such as EUDRAGIT S and EUDRAGIT L, may be used as coatingmaterials.

In general coating thicknesses of about 25 to 200 μm, and especially 75to 150 μm, are preferred using about 3 to 25 mg, preferably 8 to 15 mgof acidic coating material per cm² of tablet or capsule surface. Theprecise coating thickness will however depend upon the solubilitycharacteristics of the acidic material used and site to be treated.

Together with the acidic material, the coating material may containadditives such as coloring agents, plasticisers, opaque film coatings,gloss producers and auxiliary materials (e.g. talc).

As referred to above, the provision of the coating to the compositionsof the invention may be achieved in conventional manner, e.g. by the useof spraying, fluidized bed, immersion tube and immersion bladetechniques. (See for example D. Dreher "Film coatings on acrylic resinbasis for dosage forms with controlled drug release" PharmaInternational 1/2 (1975) 3 ).

In microgranular formulations, suitably the granules are 0.25 to 4 mm,usually 0.25 to 2.5 mm, especially 0.4 to 1.5 mm and particularly about0.6 mm, diameter.

The coating can be applied to the granules by any suitable known coatingtechnique. In particular, conventional coating techniques such as sprayor pan coating can be employed. (See for example D. Dreher, supra).Preferably, the coating is applied from aqueous suspension.

The granular coating material can be any suitable coating, e.g.cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate,ethyl cellulose or polyvinyl acetate phthalate but the preferred coatingmaterial is an anionic polymer, especially one having the dissolutionprofile specified in EP-A-0097651. The presently preferred polymers areanionic carboxylic polymers, e.g. EUDRAGIT L or S described above.

The thickness of coating required on the granules will depend upon thedissolution profile of the particular coating materials and possiblyalso upon the dissolution profile of the enteric coating on the capsule.However, it is well within the ability of the man of average skill inthe art to determine by trial-and-error experimentation the optimumthickness of a particular coating required for a particular dosage formof the invention. When using an aqueous dispersion of a partly methylesterified methacrylic acid polymer of the EUDRAGIT S type, the amountof coating material usually will be between 20 and 25% (dry weightbasis) with 21 to 23% being preferred.

The coating can, and usually will, contain plasticiser and possiblyother coating additives such as colouring agents, gloss producers, talcand/or magnesium stearate as well known in the coating art. Inparticular, anionic carboxylic acrylic polymers usually contain 10 to25% by weight of a plasticiser especially diethyl phthalate, althoughthe presence of such a plasticiser may not be necessary when using anaqueous suspension for coating.

Usually, the capsule into which the coated granules are loaded will be asoft or, preferably, hard gelatin capsule although other capsules whichwill dissolve in the small intestine can be used. The capsule is coatedwith an enteric coating which will protect it during passage through thestomach. Any conventional enteric coating material which is soluble inthe small intestine can be used, e.g. cellulose acetate phthalate,hydroxy propylmethyl cellulose phthalate or initially ethyl cellulosefollowed by polyvinyl acetate phthalate, but it is preferred to use ananionic polymer having an appropriate dissolution profile. The presentlypreferred polymers are anionic carboxylic polymers, e.g. EUDRAGRIT L.

The enteric coating can, and usually will contain plasticiser andpossibly other coating additives such as colouring agents, glossproducers, talc and/or magnesium stearate as well known in the coatingart. In particular, anionic carboxylic acrylic polymers usually contain10 to 25% by weight of a plasticiser especially diethyl phthalate.

Conventional coating techniques such as spray or pan coating areemployed to apply the enteric coating (see for example D. Dreher,supra).

In addition to the active bismuth containing compound the tablet orcapsule cores for the compositions of the present invention may alsocontain additives such as fillers (e.g. lactose or dicalcium phosphate),binders (e.g.starch or polyvinylpyrrolidone), lubricants (e.g. magnesiumstearate, stearic acid or talc) and disintegrants (e.g. alginic acid orsodium starch glycolate). The tablet or capsule cores may be prepared ina conventional manner. For some delayed release applications it will bepreferable to combine the bismuth complex in a matrix of hydrophobicpaste.

It is preferable to include a suitable disintegrant, such as Explotab (abrand of sodium starch glycollate made by K&K Greef), or Primojel (fromAVEBE, Netherlands) in the orally administered compositions according tothe invention.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLE 1

900 mg of carbomer (Carbopol 934P; B. F. Goodrich) is evenly dispersedby vigorous stirring in 100 ml of water and then 450 mg of bismuthcitrate (BPC 1949) is added with stirring. The stirring is continuedthroughout but not vigorously and a sodium hydroxide solution of knownstrength, preferably 20% w/v, is gradually added until a viscoussolution (gel) is formed and the pH is adjusted to between 6 and 7.5,although a wider pH may be used (e.g. from 5 to 8). Gentle stirring isthen continued until the reaction is complete at which time thecarbomer/bismuth complex may be extracted from the aqueous solution byprecipitation with methanol. After extraction, it may be dried andsubsequently used either in dry formulations or re-solubilised for usein an enema.

EXAMPLE 2

Bulk preparation of bismuth citrate enemas containing the followingingredients:

    ______________________________________                                        Bismuth Citrate         225 g                                                 Carbomer 934P           450 g                                                 Keltrol                 100 g                                                 Lecithin                100 ml                                                Methylhydroxybenzoate   75 g                                                  Propyl hydroxybenzoate  7.5 g                                                 Sodium Hydroxide        500 ml*                                               20% w/v                                                                       Filtered Water          to 50 l.                                              ______________________________________                                    

The carbomer and Keltrol were added gradually to rapidly stirred volumesof cold water and stirring was continued until a viscous suspension andsolution respectively were formed. Methyl and propyl hydroxybenzoate,previously dissolved in boiling water, were added to the viscous Keltrolsolution. Bismuth citrate was mixed with lecithin and added slowly tothe Keltrol solution with constant stirring. The carbomer solution wasthen added slowly with stirring; once the mixing was completeapproximately 500 ml of sodium hydroxide solution was added to bring thepH into the range 6.8-7.4 (optimal 7.0). The resulting thixotropicpreparation was distributed in 100 ml enema bags in 100 ml aliquots.

EXAMPLE 3

Bismuth citrate (225 g) was dispersed in the carbomer suspension asprepared in Example 2. The required amount of sodium hydroxide solution(20% w/v) was the added to bring the pH to about 7.0. After stirringovernight, the resulting gel was mixed with an equal volume of methanolwhich caused precipitation of the carbomer-bismuth citrate complex. Thepreparation was centrifuged and the supernatant discarded. The remainingslurry was freeze dried to produce a dry powder for later use. This drypowder, on mixture with water, readily reconstitutes a viscous gel whichis clear and pharmaceutically acceptable.

EXAMPLE 4

Samples were made with bismuth citrate (430 mg)+carbomer (900 mg)+H₂ O(100 ml)+NaOH pellets (410 mg). Following vigorous stirring this wasleft overnight to go translucent indicating that the reaction had takenplace. The gels were precipitated with methanol (150 ml to 200 ml). Thewhite precipitate was pelleted by centrifugation (1500 rpm, 30 min), thesupernatant decanted, and the precipitate freeze dried. The driedprecipitate was powdered before despatch. The content of Bi was 15.2 wt%.

Further samples were made with bismuth citrate (430 mg)+carbomer (1800mg)+H₂ O (150 ml)+NaOH pellets (900 mg). This was stirred vigorously andleft overnight to go translucent. These gels were precipitated withmethanol (250 ml). The white precipitate was pelleted and dried. Thedried precipitate was powdered before despatch. The Bi content was 8.74wt %.

EXAMPLE 5

Patients and Methods

Thirty patients with radiological or endoscopic evidence of proctitis orprocto-sigmoiditis with mildly or moderately active disease wereincluded in the study.

Enemas (100 ml) prepared according to Example 2, were given to patientsand were administered each night for four to eight weeks. Clinical andsigmoidoscopic evidence of improvement was observed in most of them.

In addition, in a controlled clinical trial these enemas were comparedwith enemas of mesalazine (2 g in 100 ml) given to similar patients for4 weeks. Sigmoidoscopy and rectal biopsy were performed initially andafter four weeks of treatment; patients kept a diary card and recordeddaily symptoms of abdominal pain, general well being and the number andconsistency of bowel motions; the presence of blood and mucus was alsonoted. Clinical and sigmoidoscopy findings were graded and blindhistological grading of all biopsies was performed.

Results with the enema of Example 2 appeared to be at least as good asthose given by the mesalazine treatment which is currently among thebest treatments for proctitis.

EXAMPLE 6

Patients and Methods

Eleven patients having radiological or endoscopic evidence of proctitisor procto-sigmoiditis with mildly or moderately active disease wereincluded in the study. The eleven patients had been in clinical relapsefor between 1 week and 3 years (median 3 months) with 9 of the 11 inrelapse for more than 2 months. Eight of the 11 patients were takingmesalazine at the time of relapse and continued to take this drug; nonewere receiving oral prednisolone or other rectal medication.

Enemas were prepared from De Nol which contains tripotassium dicitratobismuthate and has a pH of 9.8. Patients were given 300 ml of this and asecond bottle which contained a 1.2% Keltrol suspension (a thixotropicxanthan gum) with a phosphate buffer at pH4.6 and hydroxybenzoates aspreservative. Patients used a graduated measure into which was poured 20ml of De Nol and 20 ml of Keltrol--the 40 ml mixture containing 480 mgof Bismuth with a pH of 7.2 was used as the enema; these wereadministered each night for four weeks. Sigmoidoscopy and rectal biopsywere preformed initially and after four weeks of treatment; patientskept a diary card and recorded daily symptoms of abdominal pain, generalwell being and the number and consistency of bowel motions; the presenceof blood and mucus was also noted. Clinical and sigmoidoscopy findingswere graded and blind histological grading of all biopsies wasperformed.

Results

Of the 11 patients (5 men) there was symptomatic improvement in 5,whilst 6 remained unchanged. Sigmoidoscopic appearances were improved in9, with no change in 2 and histological grading improved in 6, remainedthe same in 2 and was worse in 3. Topical treatment of proctitis andprocto-sigmoiditis with bismuth enemas for four weeks improved overallscores of symptoms, sigmoidoscopic and histological appearances in 9 of11 patients studied.

EXAMPLE 7

Granules of size in the range 0.5-2.1 mm were prepared by dry compactingand subsequently sieving a tablet mass containing a complex of bismuthcitrate with carbopol 934P. The granules were then spray coated with anaqueous suspension containing EUDRAGIT L (Rohm Pharma GmbH, Darmstadt,Germany) in the ratio of 3:7 to provide a batch coated with 25% drylacquer substance. The resulting granules had the following formulation:

    ______________________________________                                        Material                                                                      ______________________________________                                        Bi/carbomer complex     55.8 g                                                Lactose                 10.7 g                                                Povidone (i.e. PVP)     1.2 g                                                 Explotab (Na Starch     2.5 g                                                 glycolate)                                                                    Mg stearate             0.9 g                                                 Talc                    10.6 g                                                EUDRAGIT L              18.1 g                                                Antifoam emulsion SE 2  0.1 g                                                 Total                   100.0 g                                               ______________________________________                                    

The batch of coated granules was packed into hard gelatin capsules(LOK-CAP, Eli Lilly) in an amount of 800 mg granules per capsule.

We claim:
 1. A water soluble complex of bismuth with a polyacrylate. 2.A complex as claimed in claim 1 wherein the polyacrylate is a carbomer.3. A complex as claimed in claim 1 or 2 wherein the bismuth andpolyacrylate are in a weight ratio of 1:7 to 5:1.
 4. A complex asclaimed in claim 1, wherein the bismuth is derived from a bismuth saltof a weak inorganic acid, a bismuth salt of a carboxylic acid, orbismuth hydroxide.
 5. A complex as claimed in claim 4, wherein thebismuth salt is selected from the group consisting of bismuth citrate,bismuth subsalicylate and bismuth subgallate.
 6. A complex as claimed inclaim 1, comprising carbopol 934P and bismuth derived from bismuthcitrate.
 7. A pharmaceutical composition comprising a complex as claimedin claim
 1. 8. A pharmaceutical composition as claimed in claim 7,including a disintegrant.
 9. A pharmaceutical composition as claimed inclaim 7, in a delayed or sustained-release dosage form for oraladministration to deliver bismuth post-gastrically.
 10. A pharmaceuticalcomposition as claimed in claim 9, in the form of microgranules coatedwith a methyl methacrylate/methacrylic acid copolymer to provide delayedrelease of the bismuth.
 11. A pharmaceutical composition as claimed inclaim 7, in a form for rectal administration.
 12. A pharmaceuticalcomposition as claimed in claim 7, further comprising one or more activeingredients.
 13. A pharmaceutical composition as claimed in claim 12,further comprising one or more pharmacologically active compoundsselected from antibiotics and anti-protozoal agents.
 14. Apharmaceutical composition as claimed in claim 13, comprisingtetracycline as said antibiotic and Metronidazole as said anti-protozoalagent.
 15. A process for the preparation of a water-soluble complex ofbismuth and a polyacrylate comprising reacting a bismuth-containingcompound with a polyacrylate in a liquid phase.
 16. A method of treatinginflammatory bowel disease which comprises the step of administering apharmaceutically effective amount of a water-soluble complex of bismuthwith a polyacrylate either orally in a delayed or sustained-releasedosage form, or rectally.
 17. A method as claimed in claim 16, whereinthe bismuth is derived from bismuth citrate, the polyacrylate is acarbomer and administration is orally in a delayed or sustained-releasedosage form.
 18. A method as claimed in claim 17, wherein the carbomeris carbopol 934P and the weight ratio is about 1:2.
 19. A method asclaimed in claim 18, wherein said water-soluble complex ismicroencapsulated.
 20. A method of treating Helicobacter pyloriinfection of the alimentary canal which method comprises the step ofadministering a pharmaceutically effective amount of abismuth/polyacrylate complex as defined in claim
 1. 21. A method asclaimed in claim 20, wherein said complex also comprises tetracyclineand Metronidazole.